This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objectives: Perform cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses;determine kinetics of CTL epitope escape/reversion in 150 transmission pairs as virus adapts in moving from one immunogenetic environment to another;determine if long-term non-transmitting partners display bias in escape signatures that contribute to lack of transmission. In two HIV C clade-infected populations in South Africa/Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in predictable order. We show accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in-vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in absence of adequate, continued CTL responses. At least some alternate reading frames in HIV-1 have potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). We analyzed HLA class I-associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with majority derived from antisense transcripts. Both sense- and antisense-encoded CEs were immunogenic at both stages of infection. In addition, CEs often mutated during first year of infection, which was consistent with immune selection for escape variants. These findings indicate that HIV-1 genome might encode and deploy a large potential repertoire of unconventional epitopes to enhance vaccine-induced antiviral immunity. Finally, results from a 9-cohort study showed the frequency of certain epitope variants was highly correlated with the abundance of the restricting HLA allele, suggesting viral adaptation to HLA pressure within the population.